Nephrology and Dialysis Unit, Postgraduate School of Nephrology, Vita Salute University, San Raffaele Scientific Institute, 20132 Milan, Italy.
Eur J Endocrinol. 2011 Mar;164(3):421-7. doi: 10.1530/EJE-10-0915. Epub 2010 Dec 23.
Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).
A genotype-phenotype association study.
In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.
The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age.
Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.
钙敏感受体（CASR）基因调控区的单核苷酸多态性（SNP）与特发性钙肾结石病有关。为了证实它们与肾结石病的相关性，我们对原发性甲状旁腺功能亢进症（PHPT）患者进行了检测。
基因型-表型关联研究。
共对 332 例 PHPT 患者和 453 例健康对照者进行了 rs7652589（G>A）和 rs1501899（G>A）SNP 的基因分型，这些 SNP 位于 CASR 基因的非编码调控区。比较了 PHPT 患者和对照组之间，以及结石形成和无结石 PHPT 患者之间的等位基因、单倍型和双等位基因分布。
PHPT 患者和对照组 rs7652589 和 rs1501899 SNP 的等位基因频率相似。这两个 SNP 的 A 等位基因在结石形成（n=157）患者中比在无结石（n=175）患者中更为常见（rs7652589：36.9%比 27.1%，P=0.007；rs1501899：37.1%比 26.4%，P=0.003）。因此，AA 单倍型（n=174，AA/AA 或 AA/GG 双等位基因）的纯合或杂合 PHPT 患者结石风险增加（优势比 1.83，95%置信区间 1.2-2.9，P=0.008）。此外，这些 PHPT 患者的血清离子钙和甲状旁腺激素浓度较高（1.50±0.015mmol/l 和 183±12.2pg/ml），高于 GG/GG 双等位基因（n=145）患者（1.47±0.011mmol/l（P=0.04）和 150±11.4pg/ml（P=0.049））。使用逻辑回归模型，PHPT 患者的结石风险增加可由 AA/AA 或 AA/GG 双等位基因、血清离子钙最高三分位数和年龄最低三分位数预测。
位于 CASR 基因调控区的多态性可能增加 PHPT 患者肾结石形成的易感性。
